The macrocyclic lactones, i.e. the avermectin and milbemycin series of compounds are potent endo- and ectoparasitic agents. The compounds which belong to this series are either natural products or are semi-synthetic derivatives thereof. The structure of these two series of compounds are closely related and they both share a complex 1,6-membered macrocyclic lactone ring; the avermectins comprise a disaccharide substituent in the 1,3-position of the lactone ring, which the milbemycins do not.
Macrocyclic lactones, e.g. ivermectin are commonly used in the veterinary science as an anti-parasitic medication. It is effective against most common intestinal worms, most mites and some lice.
To this end, it is desired to provide macrocyclic lactones in a drug delivery system that is capable of the controlled release of the active compound, preferably yielding a constant release for a prolonged period of time.
As is recognized in the art, a constant release is difficult to achieve. Most, if not all, controlled release systems will have an initially high release (burst release). The release thereafter, in a curve of release versus time, will usually show a certain degree of decline, varying from a steep linear curve (first order release) to the more desirable flat curve of near zero order release. A challenging objective is to obtain zero order release (i.e. a truly flat curve of release against time).
A reference on ivermectin implants is Maeda H., et al., “Design of controlled-release formulation for ivermectin using silicon,” Int. Journal of Pharmaceutics, 261, pp. 9-19 (2003). This reference discusses a cylindrical implant having a drug-loaded silicone matrix coated with an impermeable lateral coating (i.e., a coating everywhere except the ends). This “covered-rod” type of implant design allows drug release to occur only at the uncovered ends of the structure. The reference compares this design with a design in which the silicone core matrix is not laterally covered by an impermeable coating. It is concluded that the release from the latter implant (which can be described as “matrix release”) is first order release.
The thrust of the article is to show that the “covered rod” design is capable of approaching zero order release. However, additional measures are needed to obtain sufficient release. E.g., in order to have a near zero order release for a period of 2-3 months, it is necessary to add polyethylene glycol. Without such an additive, it can be inferred from the paper that the release is at an insufficient level.
The need to use an additive generally is a disadvantage. E.g. evidence of the additive's safety will need to be provided. Particularly for the preferred PEPPG this might require extensive toxicological investigations with an unknown outcome. Another serious drawback of substantial amounts of additives in that this will result in less space in the implant to accommodate active ingredients. For implants it is of essential importance to use high drug loads in order to retain acceptable implant dimensions. In the event that a substantial amount of the composition is made up of inactive additives this will result in larger implant dimensions.
To the person skilled in the art, it is further recognizable as a drawback if the release characteristics are dependent on the inclusion of additives, rather than on the choice of implant carrier material. This complicates the manufacturing process, and it goes against a general desire to keep the number of additives low. Furthermore, the need for additives that affect release, leads to a lower degree of freedom to include other additives (that may be needed for other purposes), as in such a system any change in the composition goes with the risk of deteriorating the release characteristics.
In the case of drug-loaded implants this e.g. means that one has a lower degree of freedom to include useful additives such as radiocontrast agents. The latter, e.g. barium sulfate, are important tools to locate an implant in events where its quick removal is required. This is of recognized importance for drug delivery systems that provide prolonged release. E.g. if an animal experiences an adverse event as a result of taking a single dosage of an immediate-release drug, the administration of the drug can simply be discontinued. If, however, these circumstances take place in the case of an implant, providing prolonged release, it will be necessary to remove the implant. For this purpose, it is important that the implant can be located in the body. To this end X-ray is the most suitable technique. This requires X-ray visibility of the drug delivery system, which is attained by the inclusion of a radiocontrast agent. Further, drug delivery systems such as disclosed by Maeda et al. in which the release characteristics are dependent on a structure of pores or channels, and in which the release has to be tuned by means of additives, are relatively complicated from a process and design point of view. The covered rod as disclosed in Maeda et al is basically a matrix containing water soluble drug(s) and optionally also water soluble excipients. This matrix is covered by a water impermeable skin. The mechanism of release is the ingress of water via the open terminal ends and the drug is slowly released in a near zero order fashion only via the terminal ends. As a result of water ingress and the dissolution of water soluble material an open porous channel structure is formed. The purpose of the water impermeable skin is to prevent release via the lateral side.
The present invention is a drug delivery system of the reservoir type. The reservoir is essentially non-porous and drug release is not driven by the ingress of water into the system. Instead the release mechanism is based on diffusion of drug molecules through a non-porous polymer medium. In the interior of the dosage form e.g. the implant—contrary to a covered rod design—water does not play a role in the diffusion process. Hence dissolution via the open ends is only marginally contributes to the steady state release of the system and release predominantly takes place via the lateral rate controlling skin.
The big advantage is that the release is proportional to the surface area of the lateral side and hence for a chosen diameter to the length of the implant.
Moreover, in Maeda et al, zero order release kinetics is not observed in vivo.
It would be desired to provide a drug delivery system for the controlled release of a macrocyclic lactone that is capable of releasing the macrocyclic lactone for an extended period of time, and preferably at a constant level of release. It would also be desired to provide a drug delivery system for the controlled release of a macrocyclic lactone that can be manufactured in a simple, straightforward process. It would further be desired to provide a drug delivery system for the controlled release of a macrocyclic lactone that has a good tolerance for the inclusion of additives, and that particularly allows the inclusion of a radiocontrast agent.
Another drawback of the “covered rod” type of implant is that it is essentially not protected against dose-dumping. This refers to the untimely, and unwanted, release of large amounts of the dose contained in the implant, if it is damaged before or upon insertion. Thus, e.g. cutting a covered rod into two pieces will inevitably result in doubling of the release as well as early depletion. The latter is particularly disturbing while unanticipated early depletion will leave the implant carrying animal unprotected. The reservoir type implant according to the invention is substantially resistant against dose dumping. Cutting the implant in half does not substantially affect the release rate. While in case of the covered rod design—realising that release is proportional surface area exposed to the watery environment e.g. body fluids—damage to the skin will immediately result in a largely increased release rate.
Based on the teaching of Maeda et al., the person skilled in the art will have difficulty finding a system that addresses the foregoing desires. For, the authors teach that for ivermectin a new method of release control is necessary, as compared to matrix release of proteins. This is consistent with other authors. E.g. a further background to drug delivery systems for controlled release can be found in a paper by Rajan Bawa et al., Journal of Controlled Release 1 1985 p 259-265. With reference to release systems based on biocompatible polymers such as ethylene-vinyl acetate copolymer, it is indicated that these polymers are impermeable to molecules larger than 600 Da (g/mole). It is further described that in these cases release can be obtained, provided that a tortuous, interconnected pore network be formed. This is well-recognized by specialists in the field, as is apparent from another background reference, “New methods of Drug Delivery”, Robert Langer, Science, 249 (4976) 1990, 1527-1533. This author confirms that drugs to be released need to have a molecular weight below 600, and supports that large molecules can be released via the formation of a porous path.
Based on the foregoing, the person skilled in the art faces difficulty when addressing the controlled release of macrocyclic lactones, which have molecular weights above the critical upper limit of 600. E.g. moxidectin has a molecular weigh of about 640 g/mole and ivermectin is as high as 875 g/mol.
As a further background on attempts to provide macrocyclic lactone implants, reference is made to BR PI0504244. This document describes, in general terms, subcutaneous implants of ethylene vinyl acetate and polydimethyl siloxane (silicone). The implant essentially is made by first mixing the active ingredient with silica, and then with the polymer or silicone. Although the document does not provide enough detail to enable actually making an implant based on the described technology, it is clear that the active ingredient is not taken up into a continuous polymeric matrix, but in a system having a silica phase. The silica should be expected to serve the creation of a network of interconnecting particles, as the percolation threshold (the point at which particle interconnection will occur) typically is low for high surface area materials such as silica's. This effectively generates a porous path through the matrix, and this too speaks against release from the macrocyclic lactone through the polymer itself.
Another reference is WO 03/002102. This document relates to silastic-based mini implants for the sustained release of active substances. In recognizing the aforementioned danger of dose-dumping, the document provides a more ore less mechanical solution. Rather than seeking formulation technology to help in preventing dose-dumping, the document describes a sustained release apparatus including a plurality of mini-implants or pellets. Thus, the aforementioned danger is contained by the sheer small size of the individual implants. This is practically cumbersome, and far from the ideal of a single implant with a long duration of action. The mini implants are disclosed for a great many active compounds.
Yet another desire, not satisfied in the art, is to provide a drug delivery system, preferably an implant that allows an extended release, of one year or more, of the macrocyclic lactone compound and preferably of at least 1.5 to 3 years. Particularly, it is desired to provide such an extended release drug delivery system that, during the aforementioned periods of use, exhibits near zero order release.